STRUCTURE AND FUNCTION OF RECEPTORS AND TRANSPORTERS AT CHEMICAL SYNAPSES

化学突触受体和转运蛋白的结构和功能

• 批准号: 8361620
• 负责人: James E Gouaux
• 金额: $ 9.32万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2012-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8361620
• 关键词: Agonist; Binding; Chemical Synapse; Development; Eukaryota; Funding; Gated Ion Channel; Glutamate Receptor; Glutamates; Grant; Human; Integral Membrane Protein; Ion Channel; Length; Ligands; Light; Moods; National Center for Research Resources; Nervous system structure; Nicotinic Receptors; P2X-receptor; Physiology; Play; Principal Investigator; Rattus; Reporting; Research; Research Infrastructure; Resolution; Resources; Role; Source; Structure; Synaptic Transmission; Therapeutic Agents; United States National Institutes of Health; Zebrafish; cost; novel therapeutics; receptor; receptor structure function; structural biology

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. This proposal involves three different and unique integral membrane proteins: (1) a eukaryotic pentameric 'Cys-loop' receptor; (2) a eukaryotic P2X ion channel; and (3) a eukaryotic, full-length ionotropic glutamate receptor (iGluR). We are studying the structure and function of so-called Cys-loop receptors of which the nicotinic acetylcholine receptor is perhaps the most well known example. These pentameric, ligand-gated ion channels play essential and widespread roles in human physiology, particularly in the nervous system, and are the targets of a broad spectrum of therapeutic agents and mood altering substances. We have crystals of a eukaryotic Cys-loop receptor that diffract to 3.2 ¿ resolution. The second project is focused on full-length P2X receptors. P2X receptors are ATP-gated ion channels that are present only in multicellular eukaryotes and that play key roles in nervous system. Last year we reported the structure of the zebra fish P2X4 receptor in an apo, closed state. Now we aim to solve structures in other functional states: open; closed-desensitized; closed-antagonist bound. These structures will not only shed light on the mechanism of P2X receptors but they may also facilitate the development of novel therapeutic agents. The third project involves studies of crystals of glutamate-gated ion channels, the linchpins of fast synaptic transmission in the human nervous system. Last year we also reported the first structure of the rat GluA2 AMPA-sensitive receptor in an antagonist-bound, closed state. Now we aim to solve the structures of the receptor in multiple functional states, including the agonist-bound, desensitized state and the agonist-bound open state.

该副本是利用资源的众多研究子项目之一 由NIH/NCRR资助的中心赠款提供。对该子弹的主要支持 而且，副投影的主要研究员可能是其他来源提供的 包括其他NIH来源。列出的总费用可能 代表subproject使用的中心基础架构的估计量， NCRR赠款不直接向子弹或副本人员提供的直接资金。 该建议涉及三种不同且独特的整合膜蛋白：（1）真核五聚体“ Cys-Loop”受体； （2）真核P2X离子通道； （3）真核，全长离子型谷氨酸受体（Iglur）。 我们正在研究所谓的CYS环受体的结构和功能，其中烟碱乙酰胆碱受体可能是最著名的例子。这些五聚体门控离子通道在人类生理学（尤其是在神经系统中）起着必不可少的和宽度的作用，并且是广泛的治疗剂和改变情绪的物质的靶标。我们有一个真核Cys-loop受体的晶体，衍射为3.2`分辨率。 第二个项目集中在全长P2X受体上。 P2X受体是仅在多细胞真核生物中存在的ATP门控离子通道，并且在神经系统中起关键作用。去年，我们报道了斑马鱼P2X4受体在Apo封闭状态下的结构。现在，我们旨在解决其他功能状态的结构：开放；封闭式敏感；封闭式抗议者绑定。这些结构不仅会阐明P2X受体的机制，而且还可以促进新型治疗剂的发展。 第三个项目涉及研究谷氨酸门控离子通道的晶体，即人类神经系统中快速突触传播的关键。去年，我们还报道了在拮抗剂结合的封闭状态下，大鼠GLUA2 AMPA敏感受体的第一个结构。现在，我们旨在在多种功能状态下解决受体的结构，包括激动剂结合，脱敏状态和激动剂结合的开放状态。